DESCRIPTION (the applicant's description verbatim): The overall goal of this research project is to identify the functional role of human myotonic dystrophy protein kinase (DMPK) in myocardium. DMPK was the first identified member of a novel family of multi-domain serine-theronine protein kinases defined by a unique kinase core and common non-catalytic domains. Physiological substrates and functions for most members of this kinase family are unknown. DMPK was originally identified when a CTG triplet repeat sequence located in the 3' untranslated region of the DMPK gene was identified and shown to be expanded in patients with myotonic dystrophy (DM). DM is an autosomal dominant myopathy with pleiotropic effects including skeletal muscle weakness and wasting, a cardiomyopathy with cardiac conduction abnormalities and myocardial dysfunction, frontal baldness, and cataracts. The pathophysiology of DM is not understood, and a number of mechanisms-including reduced DMPK expression, RNA splicing defects, and reduced expression of a homeobox gene-have been postulated to explain this complex phenotype. DMPK mRNA and protein expression is greater in myocardium than in any other tissue type implying the presence of a previously unknown protein kinase mediated signal transduction pathway in myocardium. We hypothesize that DMPK is a multifunctional protein kinase and is a component of a previously uncharacterized myocardial and skeletal muscle signal transduction pathway. Alterations in the DMPK signaling pathway are likely to be responsible for at least a portion if not all of the pathophysiology of myotonic dystrophy. This hypothesis cannot be directly tested without a better understanding of fundamental properties of the kinase including DMPK enzymatic activity, domain structure and interacting proteins. We will use biochemical analysis and molecular biology techniques to characterize DMPK enzymatic activity and autophosphorylation, identify potential physiologic substrates, define DMPK domain function, determine the effect of DMPK proteolytic processing on enzyme function and localization, and determine the functional relationship of DMPK to other members of this kinase family.